The problem of alcohol use disorders in American Indians has been addressed in three family linkage datasets: SW tribe; Eastern Oklahoma tribe with low prevalence of alcoholism; Plains Indian tribe with neuropsychological data EEG - analytical studies in progress and the Ten-Tribes dataset. In addition, LNG is the genetics collaborating laboratory on the first pharmacogenetic study on alcoholism treatment response to naltrexone and sertraline. This study on Alaska Natives, led by S. O'Malley Yale, showed that the efficacy of naltrexone in alcoholism treatment extends to Native Americans (OMalley et al, 2008). These projects include detailed psychiatric assessment with semi-structured psychiatric interviews, contrast between tribes differing in prevalence of alcoholism, study of cross-population variation in allele and haplotype frequencies, case-control association and family meiotic linkage analyses, examination of the role of individual differences in cultural experience, and - in two of the studies- the extensive use of EEG, ERP and heart rate variability intermediate phenotypes. The ability to psychiatrically assess and compare psychiatric pathology in American Indians with other populations was recently exemplified by our report on schizophrenia, a disease that is familially associated with alcoholism, in two American Indian populations (Robin et al, 2007). We have identified genetic variation in several candidate genes that appear to alter vulnerability to alcoholism or alcohol-related traits such as anxiety and impulsivity. These genes include COMT, the GABAA alpha 2 subunit and other GABAA receptor genes, DRD2, HTR1B and Galanin. In a recent gene x environment interaction study we showed that women who were sexually traumatized as children are at enhanced risk for alcoholism and antisocial personality, but much more so if they have the low expression MAOA genotype previously associated with behavioral dyscontrol. Whole genome scans were performed in two tribes. The first was conducted with 517 STR loci genotyped in a SW Indian family (N=582) that comprises a sizeable fraction of a Southwestern tribe with a high rate of alcoholism (85% of males, greater than 50% of females). The SW tribe genome scan detected two potential new loci for alcoholism: the DRD4 region at the chromosome 11p telomere, and the region of the GABAA cluster near the chromosome 4p centromere. The linkage hotspot in the GABA receptor cluster region on Chr4 was followed up with high density mapping, revealing a linkage disequilibrium signal at the GABA alpha 2 gene. This is in line with results from investigators at the University of Connecticut and the University of Indiana except that we were also able to show that the GABAA alpha 2 effect is apparently anxiety-mediated. A whole-genome scan using 5861 array-genotyped SNPs was performed on the Plains Indian tribal family (Enoch et al, 2008). The genome-wide or significant or near-significant findings we have discovered are detailed in the report AA000280-19. In a GWAS study in this same Plains Indian dataset, we recently found several genome-wide significant loci for alcoholism-associated resting EEG traits (Hodgkinson et al, PNAS, 2010). In addition to gene discovery, we have also shed some light on the meaning and consequences of alcoholism in American Indians. The same patterns of psychiatric comorbidity seen in the general U.S. population National Comorbidity Survey are seen in Indian alcoholics, indicating that the diagnosis is capturing a similar set of clinical problems. Binge drinking in American Indians is neither benign nor beneficial. Almost all of the large fraction of SW Indians who were binge drink were also alcoholic, and binge drinkers tended to become alcoholic at a younger age. Regardless of whether binge drinkers met criteria for alcoholism, they were dramatically worse in each of four symptom categories evaluated in the SADS-L:social, work, violence/lawlessness and physical. These results help lay to rest the misconception that drinking, particularly binge-drinking, is other than deleterious to American Indians and regardless of whether binge drinking is culturally determined or congruent. Finally, stress/trauma - common in these communities and often a consequence of alcoholism and heavy alcohol use, was shown to be critically important risk element in the development of alcoholism and other psychiatric disorders. These findings, were originally reported from the SW Indian tribe, and then replicated in the Ten Tribes dataset (Yuan et al). Recently, we have expanded genomic analyses to the study of rare and uncommon variants, via exome sequencing. These studies on rare variants are enhanced by the founder characteristics of American Indian populations, and can uniquely benefit these populations in instances where the rare variant is largely population restricted. These studies have also been enhanced by availability of extensive exome data within LNG, and in public databases such as EXAC and GNOM, and because of the complementary genetic linkage findings we have made in American Indians, implicating genes and chromosomal regions.